Mice with the p53 tumor suppressor gene knocked out by gene targeting develop normally but have increased susceptibility to spontaneous tumorigenesis. We have reported that dietary interventions such as calorie restriction (CR; a potent inhibitor of many types of rodent tumors) and the chemopreventive agents dehydroepiandrosterone (DHEA) and its derivative 6-alpha-fluoro-5-androsten-17-one (8354) can offset the increased risk of tumorigenesis resulting from the loss of tumor suppressor function and thus significantly delay tumor development in these genetically susceptible mice. In studies with ex vivo tissues and cells from these mice (studies designed to define the diet-gene interactions underlying efficacious interventions), CR, DHEA and 8354 each suppressed macrophage nitric oxide production, suggesting that a common denominator of interventions which suppress spontaneous tumorigenesis in p53-deficient mice is the ability to decrease oxidative stress. Other studies on molecular and immunohistochemical markers of proliferation and apoptosis indicated that CR and DHEA differentially modulate these two determinants of cell number homeostasis. Recent studies indicate that in the thymus DHEA and 8354 modulate thymocyte maturation at an early stage. Ongoing projects include dietary prevention studies in heterozygous p53- deficient mice, which retain one wild-type allele of the p53 tumor suppressor gene and have a longer latency to tumor development than mice completely lacking p53. The heterozygote may be a good model for the Li- Fraumeni familial cancer syndrome, which in many kindreds has been shown to be associated with a germ-line p53 mutation. We are finding that CR appears to be effective in male heterozygous p53-deficient mice even when started at a much older age. The effect of DHEA in these animals, if any, is less clear. However, in older female heterozygous p53- deficient mice, compound 8354 (which lacks the harmful androgenic side- effects of DHEA) is proving to be effective in delaying development of certain sarcomas.